Process for the preparation of optically-active carbazole derivatives, new R- and S-carbazole derivatives and pharmaceutical compositions containing these compounds

ABSTRACT

A process for the preparation of S- or R-carbazole derivatives of the general formula: ##STR1## in which R is an unsubstituted or substituted amino radical and pharmacologically acceptable salts, by either reacting R-(-)-epichlorohydrin (for the S-carbazole derivative); or reacting an S-epoxide derivative of the general formula: ##STR2## in which R 1  is the residue of a substituted sulphonic acid derivative (for the R-carbazole derivative); with 4-hydroxycarbazole and then with ammonia or a substituted amine of the general formula RH, and recovering the compound or converting it to a pharmacologically acceptable salt. 
     The new R-(+)- and S(-)-carbazole derivatives provided by the inventive process have unexpected beta blocking and vasodilatory properties and are useful in pharmaceutical compositions. R-(+)-carbazole derivatives are also useful for the treatment of glaucoma.

This application is a divisional of Ser. No. 049,673, filed May 13,1987, now U.S. Pat. No. 4,824,963, which is a divisional of Ser. No.612,255, filed May 21, 1984, now U.S. Pat. No. 4,697,022.

The present invention is concerned with a process for the preparation ofoptically-active carbazole derivatives, with new R- and S-carbazolederivatives and with pharmaceutical compositions containing thesecompounds.

Thus, according to the present invention, there is provided anasymmetric synthesis, with high optical purity, of R- and S-carbazolederivatives of the general formula: ##STR3## in which R is anunsubstituted or substituted amino radical, as well as of theirpharmacologically acceptable salts.

In general formula (I), R is preferably an amino radical which issubstituted by a lower alkyl radical, with up to 6 carbon atoms such asa methyl, ethyl, isopropyl or tert.-butyl radical or is the radical:##STR4## in which R₂ is a hydrogen atom, a lower alkyl radical or abenzyl, phenylethyl or phenylpropyl radical, R₃ is a hydrogen atom or alower alkyl radical, R₄ is a hydrogen atom or a lower alkyl radical, X avalency bond, a --CH₂ -- group or an oxygen or sulphur atom, Ar is aphenyl, naphthyl, indanyl, tetrahydronaphthyl or pyridyl radical and R₅and R₆, which can be the same or different, are hydrogen or halogenatoms, lower alkyl radicals, aminocarbonyl groups, hydroxyl groups,lower alkoxy radicals, benzyloxy radicals, lower alkylthio radicals,lower alkylsulphinyl radicals or lower alkylsulphonyl radicals ortogether represent a methylenedioxy radical.

The lower alkyl radicals R₂, R₃, R₄, R₅ and R₆ and the lower alkoxy,lower alkylthio, lower alkylsulphonyl or lower sulphonyl radicals R₅ andR₆ suitably have 1 to 6 and preferably 1 to 4 carbon atoms.

Compounds with the above-mentioned substituents R are described inFederal Republic of Germany Patent Specification No. 22 40 599 and inEuropean Patent Specification No. 4920.

According to the processes set out in these Patent Specifications, inall cases racemates of the described compounds are obtained. Aseparation of the racemate into the optically-active antipodes takesplace according to per se known methods via a diastereomeric splittingwith the use of known, optically-active acids or bases. This process isvery laborious and, as a rule, does not give pure optically-activesubstances, contaminations due to the other antipodes being practicallyunavoidable.

Therefore, it is an object of the present invention to provide asynthesis route for the preparation of the antipodes in pure form.

Thus, according to the present invention, for the preparation ofR-carbazole derivatives of general formula (I), an S-epoxide of thegeneral formula: ##STR5## in which R₁ is the residue of a substitutedsulphonic acid derivative, is reacted with 4-hydroxycarbazole in thepresence of an organic solvent in an alkaline medium and theR-4-(2,3-epoxypropoxy)-carbazole obtained is reacted with ammonia or asubstituted amine of general formula RH, in which R has the same meaningas above, whereafter the compound obtained is, if desired, convertedinto a pharmacologically acceptable salt.

Substituted sulphonic acids in respect to R₁ are methanesulphonic acid,p-toluenesulphonic acid and benzenesulphonic acid.

The corresponding S-carbazole derivatives of general formula (I) areobtained in similar manner. For this purpose, R-(-)-epichlorhydrin isfirst reacted with 4-hydroxycarbazole in the presence of an organicsolvent in an alkaline medium and the S-4-(2,3-epoxypropoxy)-carbazoleobtained is reacted with ammonia or a substituted amine of the generalformula RH, in which R has the same meaning as above, whereafter thecompound obtained is, if desired, converted into a pharmacologicallyacceptable salt.

The preparation of the key compounds of general formula (II), preferablyof the mesyl derivative, and of the R-(-)-epichlorhydrin are describedin the literature (see Baldwin, J. org. Chem., 43, 4876/1978). Accordingto this reference, D-mannitol is converted with acetone in the presenceof zinc chloride into 1,2,5,6-di-O-isopropylidene-D-mannitol, splittingof which with sodium metaperiodate and subsequent immediate reduction ofthe intermediate aldehyde function formed givesS-(+)-isopropylidone-glycerol. Tosylation of this substance gives theR-3-tosyloxypropanediolacetonide which, without isolation, isimmediately converted into R-(-)-3-tosyloxy-1,2-propanediol. From this,by reaction with sodium methylate, there is obtained R-glycidol which,because of the danger of racemisation, is immediately reacted withmethanesulphonyl chloride to give S-(+)-3-mesyloxy-1,2-epoxypropane.

For preparation of the R-(-)-epichlorhydrin,S-(+)-3-mesyloxy-1,2-epoxypropane is opened with hydrochloric acid togive R-1-chloro-2-hydroxy-3-mesyloxypropane which, without purification,is reacted in ethylene glycol with sodium methylene-glycolate to giveR-(-)-epichlorhydrin.

The two mentioned key substances are each reacted with4-hydroxycarbazole, with reversal of the configuration, to give thepreviously unknown R-(-)-4-(2,3-epoxypropoxy)-carbazole andS-(+)-4-(2,3-epoxypropoxy)-carbazole, which are also the subject of thepresent invention. The processes give both new antipodes with an opticalpurity of almost 100%.

The optically-active antipodes of 4-(2,3-epoxypropoxy)-carbazole arereacted, with maintenance of the configuration, with appropriate aminesto give the optically-active compounds of general formula (I). For thispurpose, as a rule, the carbazole derivative is heated under reflux fora comparatively long time with amine in an organic solvent, for examplemethanol, ethanol or isopropanol.

The optically-active carbazole derivatives of general formula (I) arenew compounds. The pharmacological effectiveness of the particularantipodes is, in comparison with the racemate, greatly different.Whereas, for example, in the case of carvedilol, onlyS-(-)-(1-carbazole-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol(laevorotary isomer: Example 8) displays β-blocking properties, thevasodilatory action is present in both isomers of this compound (see thefollowing experimental report). On the basis of this fact, the differingpharmacological properties are utilised in the development ofpharmaceutical compositions.

By means of the freely selectable mixing ratios of the R andS-enantiomers, the particularly most favourable relationship of the twoactivity qualities can be objectively adjusted.

EXAMPLE

If, in the case of a racemate, the β-blockage, carried by theS-enantiomer, in comparison with the blood pressure lowering, carried bythe R- and S-enantiomers, is too strong, then a more balanced activityrelationship can be achieved by alteration of the proportion of theS-component.

Consequently, there can be used mixtures of R:S of from 1:99 to 99:1except, in the meaning of the present invention, the ratio of 50:50(racemate).

EXPERIMENTAL PROTOCOL

The β-blocking action was determined on awake rabbits on the basis ofthe inhibition of isoprenaline tachycardia (according to the method ofBartsch et al. (Experiments in animals on the pharmacological effects ofmetipranolol in comparison with propranolol and pindolol--Drug, Res., 27(II), 12, 2319-2322/1977).

As a measure for the β-blocking activity strength, there was calculatedthe 50% inhibiting dosage.

VASODILATION (MEASURED AS DIRECT BLOOD PRESSURE LOWERING AFTER A SINGLEADMINISTRATION)

In awake, spontaneously hypertonic rats (SHR), catheters were implantedin the arteria femoralis and the vena jugularis. Via the veins, therewere injected appropriate dosages of the enantiomers (R-carvedilol andS-carvedilol in dosages of 0.03; 0.1; 0.3; 1.0 and 3 mg/kg. i.v.) andthe arterial blood pressure lowering was determined via the arterialpressure catheter (as an expression of the vasodilation). As a measureof the anti-hypertensive effect, there were calculated the dosages forlowering of the blood pressure by 30 mm.Hg.

RESULTS

The results of the investigations, not only with regard to theβ-blockade but also to the blood pressure and blood vessel action, aresummarized in the following Table:

                  TABLE                                                           ______________________________________                                        Action of R- and S-carvedilol on the heart (β-blockade) and blood        vessels (blood pressure)                                                               β-blockade                                                                            vasodilation                                                              ED.sub.50 %      ED.sub.-30 mm Hg                           purity %   r      (mcg/kg i.v.)                                                                             r    (mcg/kg i.v.)                              ______________________________________                                        R-carvedilol                                                                             0.96   3980        0.97 2960                                       (>99.4%)                                                                      S-carvedilol                                                                             0.99    25         0.96  270                                       (>99.4%)                                                                       ##STR6##  --      160        --    11                                        ______________________________________                                         carvedilol =                                                                  (1carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol;           racemate                                                                 

According to the above results, with correlation coefficients (r) offrom 0.96 to 0.99, there is given a very good dosage actionrelationship. With regard to the β-blockade, between the two enantiomersthere is such a great difference that practically only S-carvedilol canbe regarded as being a β-blocker. Only at a 160 fold higher dosage in aβ-blockade detectable for R-carvedilol, which is possibly to beattributable to traces of S-carvedilol.

With regard to the blood pressure lowering action, a comparatively smalldifference is ascertainable between S- and R-carvedilol. The differencefactor is 11 and the absolutely necessary dosage in order to achieve ablood pressure lowering of 30 mm.Hg is, in the case of S-carvedilol with270 mcg./kg. i.v., in comparison to the β-blockage, about 10 timeshigher.

A further particularity of the different pharmacological properties ofthe enantiomers of a compound of general formula (I) is that only theR-enantiomers display an outstanding antiglaucoma action and, therefore,can be used as optically pure substances for the treatment of glaucoma.

For the conversion of the compounds of general formula (I) into theirpharmacologically acceptable salts, these are reacted, preferably in anorganic solvent, with the equivalent amount of an inorganic or organicacid, for example hydrochloric acid, hydrobromic acid, phosphoric acid,sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid.

For the properties of pharmacological compositions, the compounds ofgeneral formula (I) are mixed in known manner with appropriatepharmaceutical carrier materials, aroma, flavouring and colouringmaterials and formed, for example, into tablets or dragees or, with theaddition of appropriate adjuvant materials, suspended or dissolved inwater or an oil, for example olive oil.

For the treatment of glaucoma, compounds of general formula (I) or theirpharmacologically acceptable salts are used in the form of eye drops. Itis preferred to use salts with physiologically acceptable inorganic ororganic acids, for example hydrochloric acid, hydrobromic acid,phosphoric acid, sulphuric acid, acetic acid, salicylic acid, citricacid, benzoic acid, naphthoic acid, o-acetoxybenzoic acid, adipic acidor maleic acid.

It is preferred to use isotonic solutions with a pH of about 7.0. Asmedium, it is preferred to use water which can contain conventionaladditives, such as preserving agents, solubilising agents or buffers.The preserving agent is preferably benzyl alcohol, benzalkoniumchloride, phenol or chlorhexidine acetate. The solubilising agent isespecially a polyethylene glycol, polyvinylpyrrolidone or glycerol. Asbuffers, it is preferable to use acetic acid/sodium acetate, citricacid/sodium citrate or sodium EDTA.

The compounds of general formula (I) according to the present inventionand their salts can be administered enterally or parenterally in liquidor solid form. As injection medium, water is preferably used whichcontains the additives usual in the case of injection solutions, such asstabilising agents, solubilising agents or buffers. Such additives are,for example, tartrate and citrate buffers, ethanol, complex formers(such as ethylenediamine-tetraacetic acid and its non-toxic salts) andhigh molecular weight polymers (such as liquid polyethylene oxide) forviscosity regulation. Solid carrier materials are, for example, starch,lactose, mannitol, methyl cellulose, talc, highly dispersed silicicacids, high molecular weight fatty acids (such as stearic acid),gelatine, agar-agar, calcium phosphate, magnesium stearate, animal andvegetable fats and solid high molecular weight polymers (such aspolyethylene glycols). Compositions suitable for oral administrationcan, if desired, contain flavouring and sweetening materials.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1 S-(+)-3-Mesyloxy-1,2-epoxypropane

10.5 g. R-Glycidol are dissolved in a mixture of 23.3 ml. triethylamineand 210 ml. anhydrous toluene. To this is added dropwise at 0° to 5° C.,with stirring, a solution of 11.5 ml. methanesulphonyl chloride in 50ml. anhydrous toluene, whereafter the reaction mixture is left to standovernight in a refrigerator. It is then filtered off with suction andthe filtrate is evaporated in vacuo. The residue is dissolved inmethylene chloride, the solution is washed with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate solution and water, driedover anhydrous sodium sulphate and evaporated. The residue is distilled.Yield: 9g. S-(+)-3-mesyloxy-1,2-epoxypropane; b.p.: 100° C./0.8 mm.Hg;[α]₂₀ ^(D) : +24.4° (c=2.9; methanol).

The R-glycidol used is prepared as follows:

(a) 1,2,5,6-Di-O-isopropylidene-D-mannitol

To 2350 ml. acetone dried over neutral aluminium oxide are added 200 ml.molecular sieve 3 Å. 456 g. Zinc chloride are slowly introduced, whilestirring, the solution thereby warming up slightly, whereafter thereaction mixture is left to stand overnight at ambient temperature.Subsequently, 285 g. D-(-)-mannitol are introduced, while stirring, andstirring is continued for 3 hours at ambient temperature, the mannitolthereby going into solution. The reaction mixture is filtered withsuction, the filter residue is washed with a little dry acetone and thesolution is immediately added, with stirring, to a mixture of 570 g.potassium carbonate, 600 ml. water and 1700 ml. diethyl ether.Precipitated zinc carbonate is filtered off and the filtrate isevaporated. The residue is taken up in methylene chloride and the waterstill present is separated off. Subsequently, the methylene chloridesolution is dried over anhydrous sodium sulphate, treated with fuller'searth (floridin) and substantially evaporated. 3 Liters cyclohexane arethen added thereto and left to crystallise. For further purification,the residue is again recrystallised from cyclohexane. Yield: 200 g.1,2,5,6-di-O-isopropylidene-D-mannitol; m.p. 120°-121° C.

(b) S-(+)-Isopropylidene-glycerol

To a solution of 199 g. sodium metaperiodate in 1680 ml. water is addedportionwise, with stirring and ice cooling, in the course of 45 minutes,244 g. 1,2,5,6-di-O-isopropylidene-D-mannitol. After the addition iscomplete, stirring is continued for 15 minutes and then 5 liters ethanolare added thereto. The reaction mixture is filtered off with suction,the filter residue is then washed with ethanol and the filtrate ismixed, with slight cooling, in the course of 5 minutes, with 71 g.sodium borohydride. After further stirring for 2 hours at ambienttemperature, the pH value is adjusted with semiconcentrated acetic acidto 7.5. The mixture is left to stand for 15 minutes and then filteredoff with suction. The filter residue is discarded and the filtrate isevaporated to such an extent that no more alcohol passes over. Theremaining aqueous solution is extracted several times with methylenechloride. The combined methylene chloride phases are dried overanhydrous sodium sulphate and evaporated. The residue is distilled overa 40 cm. Vigreux column. Yield: 198.5 g. S-(+)-isopropylidene-glycerol;b.p. 45° C./0.7 mm.Hg; [α]₂₀ ^(D) : +11.6° (c=10; methanol); [α]₂₀ ^(D): +15.1° (c=100).

(c) R-(-)-3-Tosyloxypropane-1,2-diol

To an ice-cold solution of 36 g. S-(+)-isopropylidene-glycerol in 150ml. anhydrous pyridine is added portionwise, with stirring, 52 g.p-toluenesulphonyl chloride. After completion of the addition, themixture is left to stand overnight in a refrigerator. The solution isthen diluted with 150 ml. diethyl ether and washed with 1N hydrochloricacid until the aqueous phase has an acidic pH value, a total of about600 ml. 1N hydrochloric acid being needed. Subsequently, the solution iswashed twice with saturated aqueous sodium hydrogen carbonate solution,dried over anhydrous sodium sulphate, treated with floridin andevaporated. There are obtained 69.1 g. of an oily residue ofR-3-tosyloxypropanediol acetonide which, without further purification,is further reacted. The acetonide is warmed to 80° C. in a mixture of 50ml. acetone and 147 ml. 1N hydrochloric acid for 40 minutes, a clearsolution being obtained. The solution is evaporated in vacuo and theresidue is dissolved in methylene chloride. The methylene chloridesolution is dried over anhydrous sodium sulphate and evaporated. Theresidue is recrystallized from diisopropyl ether. Yield: 45 g.R-(-)-3-tosyloxypropane-1,2-diol; m.p.: 62° C.; [α]₂₀ ^(D) : -9.9°(c=7.9; methanol); [α]₂₀ ^(D) : -6.8° (c=7.5; pyridine).

(d) R-Glycidol

45 g. R-(-)-3-Tosyloxypropane-1,2-diol are dissolved in a mixture of 40ml. anhydrous methanol and 75 ml. anhydrous diethyl ether. To this isadded dropwise, with stirring, at 0° to 5° C., within the course of 20minutes, a solution of 4 g. sodium in 90 ml. methanol. The reactionmixture is further stirred for 2 hours and filtered off with suction.The filter residue is washed with diethyl ether and the filtrate isevaporated in vacuo at a bath temperature of 20° C. The residue is againtaken up in diethyl ether and the solution treated with floridin,filtered off over Celite and evaporated. 10.5 g. R-glycidol are obtainedas an oily residue. This is immediately further reacted in order toavoid a racemisation.

EXAMPLE 2 R-(-)-Epichlorhydrin

To 32.7 g. (+)-3-mesyloxy-1,2-epoxypropane are added dropwise, with goodcooling, 130 ml. concentrated hydrochloric acid. After completion of theaddition, stirring is continued for 30 minutes at ambient temperatureand the solution is then evaporated at a bath temperature of 30° C.After removal of remaining amounts of water, the solution is evaporatedseveral times after the addition of ethanol. The last residues ofsolvent are removed by application of a high vacuum. There are thusobtained 40.4 g. R-1-chloro-2-hydroxy-3-mesyloxypropane. This isdissolved in 105 ml. dry ethylene glycol. After the addition of asolution of 5.2 g. sodium in 130 ml. dry ethylene glycol, the mixture isfurther stirred for 15 minutes at ambient temperature. The resultantR-(-)-epichlorhydrin is immediately distilled from the reaction solutionby the application of a high vacuum (0.1-0.2 mm.Hg) at ambienttemperature. For the condensation of the R-(-)-epichlorhydrin, thecooler is supplied with a cooling brine with a temperature of -40° to -50° C. The collecting flask is also cooled to this temperature. Thereare thus obtained 15.7 g. R-(-)-epichlorhydrin; yield: 78%; [α]₂₀ ^(D) :-33.8° (c=1, methanol).

EXAMPLE 3 S-(+)-4-(2,3-Epoxypropoxy)-carbazole

27.5 g. 4-Hydroxycarbazole are dissolved in a mixture of 150 ml. 1Naqueous sodium hydroxide solution and 70 ml. dimethyl sulphoxide. Tothis is added at ambient temperature 13.9 g. R-(-)-epichlorhydrin,followed by stirring for 18 hours at ambient temperature. 280 ml. Waterare then added thereto, followed by stirring for 15 minutes andfiltering off with suction. The filter residue is washed with 0.1Naqueous sodium hydroxide solution and water and subsequently dissolvedin methylene chloride. The methylene chloride solution is dried overanhydrous sodium sulphate, treated with active charcoal and floridin andevaporated. The residue is purified by recrystallising twice from ethylacetate. Yield: 15.2 g. S-(+)-4-(2,3-epoxypropoxy)-carbazole; m.p.:163°-164° C.; [α]_(D) ²⁰ : +64.4° (c=1; pyridine).

From the mother liquors, there are isolated a further 6.7 g. of product;m.p.: 163°-164° C.; [α]_(D) ²⁰ : +64.5° (c=1, pyridine).

EXAMPLE 4 R-(-)-4-(2,3-Epoxypropoxy)-carbazole

21.9 g. 4-Hydroxycarbazole are dissolved in a mixture of 120 ml. 1Naqueous sodium hydroxide solution and 40 ml. dimethyl sulphoxide. Tothis is added dropwise, at ambient temperature, a solution of 18.2 g.S-(+)-3-mesyloxy-1,2-epoxypropane in 20 ml. dimethyl sulphoxide. Themixture is stirred for 7 hours at ambient temperature, 225 ml. water areadded thereto, further stirred for 15 minutes and filtered off withsuction. The filter residue is washed with 0.1N aqueous sodium hydroxidesolution and water and subsequently dissolved in methylene chloride. Themethylene chloride phase is dried over anhydrous sodium sulphate,treated with active charcoal and floridin and evaporated. The residue ispurified by recrystallising twice from ethyl acetate. Yield: 18.5 g.R-(-)-4-(2,3-epoxypropoxy)-carbazole; m.p.: 162°-163° C.; [α]₂₀ ^(D) :-63.4° (c=1; pyridine).

EXAMPLE 5 S-(-)-(1-Carbazol-4-yloxy)-3-isopropylaminopropan-2-olhydroacetate

500 mg. S-(+)-4-(2,3-Epoxypropoxy)-carbazole are dissolved in 4 ml.methanol and, after the addition of 2.8 ml. isopropylamine, the solutionis heated to 65° C. for 2 hours. It is then evaporated to dryness,taking care that no more isopropylamine is present. The residue isdissolved in 10 ml. hot ethyl acetate and the solution is mixed with0.24 ml. glacial acetic acid. Upon cooling, S-(-)-carbazole hydroacetatecrystallises out. The precipitate is filtered off, washed with ethylacetate and dried. Yield: 410 mg.; m.p. 158°-160° C.; [α]₂₀ ^(D) :-20.1° (c=1; glacial acetic acid); optical purity according to gaschromatography findings: 99.5%.

EXAMPLE 6 R-(+)-(1-Carbazol-4-yloxy)-3-isopropylaminopropan-2-olhydroacetate

18 g. R-(-)-4-(2,3-Epoxypropoxy)-carbazole are dissolved in 140 ml.methanol and, after the addition of 100 ml. isopropylamine, the solutionis heated to 65° C. for 2 hours. The solution is then evaporated todryness, further dried for 1 hour in high vacuum for the removal ofresidual isopropylamine and the residue is dissolved in 300 ml. hotethyl acetate. The ethyl acetate solution is treated with floridin and,after suction filtration, mixed while still hot with 8.6 ml. glacialacetic acid. After cooling, the precipitated crystals are filtered offwith suction. For further purification, the crystals are recrystallizedfrom ethyl acetate, with the addition of a little methanol. Yield: 23 g.R-(+)-(1-carbazol-4-yloxy)-3-isopropylaminopropan-2-ol hydroacetate;m.p.: 158°-160° C.; [α]_(D) ²⁰ : +20.2° (c=1; glacial acetic acid);optical purity: 98.6%; chemical purity: 99.97%.

EXAMPLE 7R-(+)-(1-Carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol

5g. R-(-)-4-(2,3-Epoxypropoxy)-carbazole are, together with 6.9 g.o-methoxyphenoxyethylamine, heated under reflux in 35 ml. isopropanolfor 2 hours. The solvent is evaporated off and the residue is stirredfor 2 hours with a mixture of 115 ml. toluene, 35 ml. cyclohexane and 40ml. ethyl acetate. The reaction mixture is filtered off with suction andthe residue is recrystallised from 150 ml. ethyl acetate. Yield: 3.7 g.R-(+)-(1-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol;m.p.: 121°-123° C.; [α]₂₀ ^(D) : +18.4° (c=1; glacial acetic acid).

EXAMPLE 8S-(-)-(1-Carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol

10 g. S-(+)-4-(2,3-Epoxypropoxy)-carbazole are, together with 13.97 g.o-methoxyphenoxyethylamine, heated under reflux in 70 ml. isopropanolfor 2 hours. The solvent is evaporated off and the residue is stirredfor 2 hours with a mixture of 115 ml. toluene, 35 ml. cyclohexane and 40ml. ethyl acetate. After filtering off with suction, the residue isrecrystallised from 150 ml. ethyl acetate. Yield: 7.2 g.S-(-)-(1-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol;m.p. 121°-123° C.; [α]₂₀ ^(D) : -18.4° (c=1; glacial acetic acid).

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

What is claimed is:
 1. An R-(-)-carbazole derivative of the formula##STR7## wherein R₂ is hydrogen, lower alkyl, benzyl, phenylethyl orphenylpropyl; R₃ and R₄ are each independently hydrogen or lower alkyl;X is a valency bond, --CH₂ --, oxygen or sulfur; Ar is phenyl, naphthyl,indanyl, tetrahydronaphthyl or pyridyl; and R₅ and R₆ are eachindependently hydrogen, halogen, lower alkyl, aminocarbonyl, hydroxyl,lower alkoxy, benzyloxy, lower alkylthio, lower alkylsulfinyl or loweralkylsulfonyl, or together represent methylenedioxy, or apharmacologically acceptable salt thereof.
 2. An S-(-)-carbazolederivative of the formula ##STR8## wherein R₂ is hydrogen, lower alkyl,benzyl, phenylethyl or phenylpropyl; and R₃ and R₄ are eachindependently hydrogen or lower alkyl; X is a valency bond, --CH₂ --,oxygen or sulfur; Ar is phenyl, naphthyl, indanyl, tetrahydronaphthyl orpyridyl; and R₅ and R₆ are each independently hydrogen, halogen, loweralkyl, aminocarbonyl, hydroxyl, lower alkoxy, benzyloxy, loweralkylthio, lower alkylsulfinyl or lower alkylsulfonyl, or togetherrepresent methylenedioxy, or a pharmacologically acceptable saltthereof.
 3. A compound of claim 1, which isR-(+)-(1-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]ethylaminopropan-2-olor a pharmacologically acceptable salt thereof.
 4. A compound of claim2, which isS-(-)-(1-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-olor a pharmacologically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmacologically acceptable inert carrier.
 6. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 2 and a pharmacologically acceptable inertcarrier.
 7. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 3 and a pharmacologicallyacceptable inert carrier.
 8. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 4 and apharmacologically acceptable inert carrier.